Abnormalities of corticosteroid and androgen metabolism have been reported in schizophrenia, but there have been no published studies of estradiol metabolism in this disease. Estradiol metabolism is principally oxidative, running via estrone into two alternative hydroxylation pathways: 16 alpha-hydroxylation, leading to estriol, and 2-hydroxylation, leading to 2-hydroxyestrone and 2-methoxyestrone. The recent development of the simple, rapid, specific radiometric procedure of Fishman et al. for direct measurement of the extent of 2-hydroxylation and 16Alpha-hydroxylation by quantitating the oxidation of stereospecifically labeled (16Alpha3H)-estradiol or (2-3H)-estradiol makes it practical to investigate oxidative estradiol metabolism in large numbers of patients. We have carried out preliminary studies in eight well characterized schizophrenic patients, five men and three women, with the following results: (1) the male patients showed a very marked, highly significant increase in 2-hydroxylation (mean 48% vs. 26% in controls; P less than 0.01); (2) 2-hydroxylation in the female patients did not differ significantly from normal; (3) four of the five men and two of the three women showed profoundly decreased 16Alpha-hydroxylation; the other men and women had normal values. All the patients of both sexes were taking phenothiazines and/or butyrophenones; medication may have played a causative role in the decreased 16alpha-hydroxylation that was seen consistently in patients of both sexes, but seems very unlikely to have played a role in the increased 2-hydroxylation that was seen only in male patients. A role for thyroid hyperactivity in causing the observed abnormalities is ruled out by the finding of normal plasma levels of T3, TSH, and free T4 in our patients. We propose to study 60 medicated schizophrenic patients in various diagnostic subcategories, 30 men and 30 women, and 20 patients, 10 male and 10 female, who have been off antipsychotic medication for at least 6 weeks, in order to determine whether there are consistent abnormalities of oxidative estradiol metabolism in schizophrenic patients as a group or in any diagnostic subgroup of these patients.